Characterization of complement activation in cutaneous ischemia-reperfusion (CI/R) injury, the role of MBL and C1q in Cl/R, and the mechanism of CI/R related injury

• Antragsteller: Privatdozent Dr. Marc Nicolai Busche
• Fachliche Zuordnung: Allgemein- und Viszeralchirurgie
• Förderung: Förderung von 2010 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 160117503

Tissue injury following restoration of blood flow after transient ischemia is known as ischemia-reperfusion (I/R) injury. Cutaneous ischemia-reperfusion (Cl/R) injury is a common clinical problem in multiple settings: chronic wounds, for example diabetic foot ulcers, atherosclerotic ulcers, pressure ulcers and venous stasis wounds, in addition to burn wounds and free tissue transfer in reconstructive surgery. Complement activation plays an important role in local and remote tissue injury associated with I/R. Three different complement pathways, the classical, lectin and alternative pathway, have been recognized. While the involvement of the different complement pathways in I/R injury of various organ systems (heart, kidneys, liver, gut, muscle) has been thoroughly investigated, the role of the complement pathways in I/R injury of the skin, the largest organ of the body, is not known. In a mouse model of Cl/R and using mice deficient in either C1q (inhibition of the classical pathway) or mannose binding lectin (MBL; inhibition of the lectin pathway), or effector proteins downstream of both pathways, I propose to identify the events leading to tissue destruction following experimental Cl/R. In this proposal, I will investigate the role of the complement system following Cl/R, specifically the role of MBL vs. C1q (i.e. lectin vs. classical pathway) and the mechanisms of MBL- and/or C1q dependent injury following Cl/R. I also intend to determine the role of the mouse complement components C5 and C3a and the role of natural antibodies in Cl/R injury. After identifying the major initiating pathway(s) in Cl/R, I plan to investigate the role of this (these) pathway(s) in diabetic Cl/R injury.

• DFG-Verfahren: Sachbeihilfen